PROJECT SUMMARY/ABSTRACT Over half of cancer patients receive radiation therapy during their course of treatment, but the current clinical practice of radiation oncology does not adjust volumes or doses based on molecular characteristics of an individual patient?s tumor. The existing knowledge gap between tumor biology and clinical practice limits the ability to personalize radiation therapy. Dr. Kesarwala?s long-term scientific goal is to improve the efficacy of radiation therapy by personalizing concurrent therapies and radiation volumes and doses based on metabolic characteristics of tumors. She proposes to approach this goal via investigation and characterization of the interacting effects of radiation therapy, IDH1 mutations, and hypoxia on the metabolic pathways of cancer cells. This proposal is designed to test the hypothesis that altering cancer cell metabolism can increase radiation response. The goals of this proposal are to characterize the effects of 1) radiation therapy, 2) IDH1 mutations, and 3) hypoxia on metabolic balance, and 4) develop small molecules for metabolic imaging. The results from this research will significantly improve understanding of a potential target pathway for combination drug and radiation therapy and lay the foundation for future radiation therapy clinical trials. During the mentored phase of this proposal, she will expand upon her background in molecular imaging and cell biology and her clinical training in radiation oncology with additional study of cancer cell metabolism and metabolic imaging. She will be mentored by Dr. Kevin Camphausen, Senior Investigator and Chief of the Radiation Oncology Branch at the National Cancer Institute (NCI), a translational radiation oncologist who is an expert in brain tumors and clinical trials. Her co-mentor for this proposal is Dr. Murali Krishna Cherukuri, Senior Investigator and Head of the Biophysical Spectroscopy Section of the Radiation Biology Branch at the NCI, a leader and innovator in functional magnetic resonance imaging and spectroscopy. Her training program represents a thoughtful approach to the transition to independence, combining guidance from an outstanding team of mentors and mentoring committee members with formal coursework, a strong career development plan, and the exceptional training environment of the NCI. The work outlined in this proposal will be the next step towards Dr. Kesarwala?s long-term career goal, which is to become an independent investigator working at the interface of radiation oncology, cancer metabolism, and molecular imaging.